The NF-κB regulator Bcl-3 restricts terminal differentiation and promotes memory cell formation of CD8+ T cells during viral infection

Bcl-3 is an atypical member of the I kappa B family that acts in the nucleus to modulate transcription of many NF-kappa B targets in a highly context-dependent manner. Accordingly, complete Bcl-3(-/-) mice have diverse defects in both innate and adaptive immune responses; however, direct effects of Bcl-3 action in individual immune cell types have not been clearly defined. Here, we document a cell-autonomous role for Bcl-3 in CD8(+) T cell differentiation during the response to lymphocytic choriomeningitis virus infection. Single-cell RNA-seq and flow cytometric analysis of virus-specific Bcl3(-/-) CD8(+) T cells revealed that differentiation was skewed towards terminal effector cells at the expense of memory precursor effector cells (MPECs). Accordingly, Bcl3(-/-) CD8(+) T cells exhibited reduced memory cell formation and a defective recall response. Conversely, Bcl-3-overexpression in transgenic CD8(+) T cells enhanced MPEC formation but reduced effector cell differentiation. Together, our results establish Bcl-3 as an autonomous determinant of memory/terminal effector cell balance during CD8(+) T cell differentiation in response to acute viral infection. Our results provide proof-of-principle for targeting Bcl-3 pharmacologically to optimize adaptive immune responses to infectious agents, cancer cells, vaccines and other stimuli that induce CD8(+) T cell differentiation. Author summary Effective immunity to previously encountered pathogens or vaccines depends on efficient formation of memory T and B cells. A major cornerstone is the generation of memory CD8(+) T cells, which kill cells infected with intracellular pathogens, including viruses. In addition, memory CD8(+) T cells are critical for adoptive immunotherapy to eliminate targeted tumor cells. Hence, it is essential to have a detailed understanding of pathways and molecular factors that regulate T cell differentiation/memory formation during the initial immune effector response. Here we show a critical cell-autonomous role for Bcl-3, an atypical member of the I kappa B family, in the regulation of CD8(+) T cell differentiation/memory formation during acute viral infection with lymphocytic choriomeningitis virus. We found that Bcl-3 dampens the terminal differentiation of CD8(+) T cells, which normally results in death at the end of the primary effector response, and instead, promotes the formation of memory precursor cells early on. This led to a robust memory response and much improved viral clearance upon re-challenge. Our results provide new insight into the molecular regulation of CD8(+) T cell effector response and memory cell generation, establishing Bcl-3 and its pathways as a target to optimize CD8(+) T cell effector responses to various immunogens including infectious agents, cancer cells, and vaccines.

Automated summary

Bcl-3 plays a crucial cell-autonomous role in regulating the balance between memory and terminal effector cells during CD8(+) T cell differentiation. Underexpression of Bcl-3 leads to skewed differentiation towards terminal effector cells and decreased memory cell formation, while overexpression enhances memory precursor cell formation.